While there has been significant progress in management of early stages of prostate cancer (PCa), metastatic hormone-refractory PCa has few effective therapeutic strategies available. Docetaxel, the main chemotherapeutic drug used in aggressive prostate cancer treatment, has shown limited efficacy against metastatic PCa, primarily due to invariable development of drug resistance, necessitating a thorough investigation of the mechanisms underlying this drug resistance and the development of novel, more efficacious therapies to prevent or overcome resistance. The receptor tyrosine kinase Axl has been implicated in the pathology of many cancers, including advanced PCa. In addition, upregulation of Axl has been linked to poor prognosis and resistance to therapy in several cancer types. We are now providing preliminary evidence that Axl is the key driver of resistance to docetaxel in PCa. While knockdown of Axl as well as Axl blockage by a pharmacologic Axl inhibitor sensitizes PCa cells to docetaxel, Axl overexpression reduces docetaxel efficacy in PCa cells. Moreover, we demonstrate that generation of docetaxel-resistant PCa cells results in upregulation of Axl expression, corroborating our notion that Axl plays a critical role in docetaxe resistance. We will, thus, test our hypothesis that Axl activation leads to resistance to docetaxel therapy in PCa and that inhibition of Axl will overcome, delay or prevent resistance to docetaxel in PCa. In order to decipher the precise role of Axl in docetaxel resistance and to develop a novel therapeutic strategy for advanced PCa we will, therefore, define the relevance of Axl expression/activity in docetaxel and cabazitaxel resistant PCa cells and perform a preclinical assessment of Axl inhibition to prevent, delay or overcome docetaxel resistance in androgen receptor-positive, androgen responsive and castration-resistant PCa xenografts. Detailed mechanistic analysis of Axl signaling in docetaxel-resistance will determine whether Axl-mediated activation of NF-B and MAP kinase signaling pathways is critical for inducing escape from docetaxel response. In Specific Aim 1 we will evaluate the effects of docetaxel treatment on proliferation, migration, invasion, and apoptosis of docetaxel resistant PCa cell lines lacking Axl expression. Furthermore, we will evaluate co-treatment of cells with the Axl inhibitors and docetaxel as well as pre-treatment with Axl inhibitors in order to determine if the use of Axl inhibitors sensitizes cells to docetaxel. In Specific Aim 2 preclinical in vivo assessment of docetaxel-resistant PCa xenografts will determine whether knockdown of Axl or pharmacological, targeted Axl inhibition is able to prevent, delay or overcome docetaxel resistance and enhances anti-tumor efficacy of docetaxel. Specific Aim 3 will decipher the precise molecular mechanisms and signaling pathways involved in Axl regulation of drug resistance, with an initial focus on the NF-B and MAPK cascades and androgen signaling. The proposed study of Axl as a driver of docetaxel and cabazitaxel resistance in PCa is anticipated to lead to an innovative combination therapy approach for a more effective treatment of metastatic PCa.